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Veterinary Oncology

Cancer is an uncontrolled growth of abnormal cells. It is found in animals as well as humans. There are many different types of cancer that are found in animals, symptoms are often similar to those in people (eg. abnormal swelling, unexplained weight loss, lethargy / reluctance to exercise etc). Cancer is one of the leading causes of death in companion animals such as dogs and cats, it is particularly common in animals that live 10 years or longer. If treatment is appropriate this may include chemotherapy and surgery or radiotherapy.

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Veterinary Oncology Links
Recent Publications

Veterinary Oncology Links (11 links)

Recent Publications

Bryan JN
Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health.
AAPS J. 2015; 17(3):506-12 [PubMed] Article available free on PMC after 19/02/2016 Related Publications
Fetal microchimerism is the co-existence of small numbers of cells from genetically distinct individuals living within a mother's body following pregnancy. During pregnancy, bi-directional exchange of cells occurs resulting in maternal microchimerism and even sibling microchimerism in offspring. The presence of fetal microchimerism has been identified with lower frequency in patients with cancers such as breast and lymphoma and with higher frequency in patients with colon cancer and autoimmune diseases. Microchimeric cells have been identified in healing and healed tissues as well as normal and tumor tissues. This has led to the hypothesis that fetal microchimerism may play a protective role in some cancers and may provoke other cancers or autoimmune disease. The long periods of risk for these diseases make it a challenge to prospectively study this phenomenon in human populations. Dogs get similar cancers as humans, share our homes and environmental exposures, and live compressed life-spans, allowing easier prospective study of disease development. This review describes the current state of understanding of fetal microchimerism in humans and dogs and highlights the similarities of the common cancers mammary carcinoma, lymphoma, and colon cancer between the two species. Study of fetal microchimerism in dogs might hold the key to characterization of the type and function of microchimeric cells and their role in health and disease. Such an understanding could then be applied to preventing and treating disease in humans.

Wagner S, Maibaum D, Pich A, et al.
Verification of a canine PSMA (FolH1) antibody.
Anticancer Res. 2015; 35(1):145-8 [PubMed] Related Publications
BACKGROUND: Canine prostate cancer (PC) is a highly aggressive malignancy. However, in contrast to man, neither standard screening strategies nor curative therapeutic options exist for the companion animal. A prostate-specific membrane antigen (PSMA) screening as molecular marker akin to human PC is currently not available for dogs as data on specific canine PSMA detection are contradictory.
MATERIALS AND METHODS: To evaluate an antibody for specific canine PSMA detection by western blotting (WB), lysates of three canine prostatic cell lines (CT1258, DT08/40, DT08/46) were comparatively analyzed by WB and mass spectrometry (MS) to the human cell lines VCaP, LnCaP and PC-3.
RESULTS: MS analyses of the detected canine proteins confirmed cross reactivity of the antibody clone YPSMA-1 with canine PSMA.
CONCLUSION: The MS analyses of the extracted canine protein bands proved that the YPSMA-1 clone is as well specific for canine PSMA in WB and, thus, represents a reliable tool for comparative PSMA studies.

Bushell KR, Kim Y, Chan FC, et al.
Genetic inactivation of TRAF3 in canine and human B-cell lymphoma.
Blood. 2015; 125(6):999-1005 [PubMed] Related Publications
Non-Hodgkin lymphomas (NHLs) are the most common cancer to affect pet dogs. In contrast to the many genes whose mutation contributes to lymphomagenesis in humans, relatively little is known about the acquired genetic alterations that lead to canine B-cell lymphomas (cBCLs). We performed a survey of 84 canine NHL tumors to identify genes affected by somatic point mutations. We found mutations affecting TRAF3, which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44% of tumors including a combination of somatic and rare germ-line variants. Overall, 30% of the tumors contained ≥1 somatic TRAF3 mutation. The majority of mutations are predicted to cause loss of TRAF3 protein including those impacting reading frame and splicing. To determine whether TRAF3 loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3 as a common event, affecting ∼9% of DLBCLs, and reduced expression of TRAF3 among deleted cases. This study implicates mutations affecting NF-κB activity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3 as a model of the more aggressive activated B-cell subgroup of DLBCL.

Elias MA, Duarte A, Nunes T, et al.
Influence of chemotherapy for lymphoma in canine parvovirus DNA distribution and specific humoral immunity.
Comp Immunol Microbiol Infect Dis. 2014; 37(5-6):313-20 [PubMed] Related Publications
In man, the combination of cancer and its treatment increases patients' susceptibility to opportunistic infections, due to immune system impairment. In veterinary medicine little information is available concerning this issue. In order to evaluate if a similar dysfunction is induced in small animals undergoing chemotherapy, we assessed the complete blood count, leukocytic, plasma and fecal canine parvovirus (CPV) viral load, and anti-CPV protective antibody titers, in dogs with lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) protocol, before and during chemotherapy. There was no evidence of decreased immune response, either at admission or after two chemotherapy cycles, indicating that the previously established immunity against CPV was not significantly impaired, supporting the idea that immunosuppression as a result of hematopoietic neoplasms and their treatment in dogs requires further investigation and conclusions cannot be extrapolated from human literature.

Shafiee R, Shariat A, Khalili S, et al.
Diagnostic investigations of canine prostatitis incidence together with benign prostate hyperplasia, prostate malignancies, and biochemical recurrence in high-risk prostate cancer as a model for human study.
Tumour Biol. 2015; 36(4):2437-45 [PubMed] Related Publications
The aim of this study was to evaluate the prevalence of acute and chronic inflammation, benign prostatic hyperplasia (BPH), and cancer of the prostate glands in the canine as a human model in prostate disorders. The study was carried out on 12 cases of different male dogs of terrier (50%), German shepherd (25%) breeds, and Greden (25%), and the age of the dogs ranged from 6 to 13 years (average age 7.8 ± 3.6). The bodyweight ranged from 3.6 to 7.9 kg. Signalment, clinical signs, and diagnostic tools such as ultrasonography, urinary cytology, and histopathology are presented. Dysuria was the most common clinical sign in this study and occurred in 10/12 canine (83.3%) included. Other clinical signs included lameness (5/12 canine, 41.6%) and constipation (3/12 canine, 25%). The range of duration of clinical signs was 5 days to 7 months. Moreover, in the present study, the urinary biochemical markers of different prostate lesions include blood, protein, and glucose and were detected in 11/12 cases (91.6%), 5/12 cases (41.6%), and 2/12 cases (16.6%), respectively. Taken together, sonographic data were classified into four groups based on histological diagnosis. In 7/12 cases (58.4%), the prostate appeared to have BPH lesions, and the remaining lesions included inflammation (3/12 cases, 25%), abscess (1 case, 8.3%), and adenocarcinoma (1 case, 8/3%) on ultrasound. In all cases, prostate tissue had an irregular echotexture. None of the dogs had sonographic evidence of sublumbar lymph node enlargement. Histopathologically, we looked at the prevalence of inflammation (33.3% chronic and 8.3% acute) and BPH (58.4%) in dogs of different ages and breeds, and also, we observed chronic inflammation in >20% of dogs, which was about 25% in 3 cases of the 12 cases referred. More chronic inflammation was associated with more BPH. The majority of the asymptomatic inflammation that is detected in the prostate is classified as chronic inflammation (i.e., as evidenced by the presence of monocytic and/or lymphoplasmacytic inflammatory cell infiltrates); however, acute inflammation is also observed to a lesser degree. Acute inflammation, as is typically evidenced by the infiltration of neutrophils, is classically an indicator of an infectious process. Finally, the patients included seven castrated, four castrated together with antibiotic therapy, and one castrated together with chemotherapy intact male dogs, which were treated with the mentioned cases. In conclusion, chronic prostatic inflammation could be a central mechanism in BPH progression, but the pathological features of tissue inflammation were different between BPH and prostate cancer (PCa). Nevertheless, the histological examination of prostate biopsies remains the only way to diagnose prostatic disorders.

Olin MR, Pluhar GE, Andersen BM, et al.
Victory and defeat in the induction of a therapeutic response through vaccine therapy for human and canine brain tumors: a review of the state of the art.
Crit Rev Immunol. 2014; 34(5):399-432 [PubMed] Article available free on PMC after 19/02/2016 Related Publications
Anti-tumor immunotherapy using tumor lysate-based vaccines has made great advances over recent decades. Cancer vaccines aim to elicit adaptive immune responses through various pathways by providing tumor and tumor-associated antigens with an immune stimulant or adjuvant. These anti-tumor vaccines are therefore developed as personalized treatments. Utilizing tumors as a source of vaccine antigens in immunotherapy has demonstrated promising results with minimal toxicity. However, to date, researchers have failed to overcome the overpowering immune suppressive effects within the tumor microenvironment. Immune suppression occurs naturally via multiple mechanisms. These mechanisms serve an important homeostatic role restoring a normal tissue microenvironment following an inflammatory response. Due to these suppressive mechanisms and the inherent heterogeneity of tumors, it is imperative to then elicit and maintain a specific tumoricidal response if vaccine therapy or some other combination of reagents is chosen. In this review, we focus on the historical use of tumors as a source of antigens to elicit a tumoricidal response and the limitations encountered that prevent greater success in immunotherapy. We describe the advantages and disadvantages of various vaccines and their ineffectiveness due to tumor-induced immune suppression.

Aricò A, Ferraresso S, Bresolin S, et al.
Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma.
PLoS One. 2014; 9(11):e111817 [PubMed] Article available free on PMC after 19/02/2016 Related Publications
Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (>30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (>41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRα are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL.

Shi C, Wu JB, Chu GC, et al.
Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1α/OATPs signaling axis.
Oncotarget. 2014; 5(20):10114-26 [PubMed] Article available free on PMC after 19/02/2016 Related Publications
Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.

Stadler KL, Ober CP, Feeney DA, Jessen CR
Multivoxel proton magnetic resonance spectroscopy of inflammatory and neoplastic lesions of the canine brain at 3.0 T.
Am J Vet Res. 2014; 75(11):982-9 [PubMed] Related Publications
OBJECTIVE: To describe findings of 3.0-T multivoxel proton magnetic resonance spectroscopy ((1)H-MRS) in dogs with inflammatory and neoplastic intracranial disease and to determine the applicability of (1)H-MRS for differentiating between inflammatory and neoplastic lesions and between meningiomas and gliomas.
ANIMALS: 33 dogs with intracranial disease (19 neoplastic [10 meningioma, 7 glioma, and 2 other] and 14 inflammatory).
PROCEDURES: 3.0-T multivoxel (1)H-MRS was performed on neoplastic or inflammatory intracranial lesions identified with conventional MRI. N-acetylaspartate (NAA), choline, and creatine concentrations were obtained retrospectively, and metabolite ratios were calculated. Values were compared for metabolites separately, between lesion categories (neoplastic or inflammatory), and between neoplastic lesion types (meningioma or glioma) by means of discriminant analysis and 1-way ANOVA.
RESULTS: The NAA-to-choline ratio was 82.7% (62/75) accurate for differentiating neoplastic from inflammatory intracranial lesions. Adding the NAA-to-creatine ratio or choline-to-creatine ratio did not affect the accuracy of differentiation. Neoplastic lesions had lower NAA concentrations and higher choline concentrations than inflammatory lesions, resulting in a lower NAA-to-choline ratio, lower NAA-to-creatine ratio, and higher choline-to-creatine ratio for neoplasia relative to inflammation. No significant metabolite differences between meningiomas and gliomas were detected.
CONCLUSIONS AND CLINICAL RELEVANCE: (1)H-MRS was effective for differentiating inflammatory lesions from neoplastic lesions. Metabolite alterations for (1)H-MRS in neoplasia and inflammation in dogs were similar to changes described for humans. Use of (1)H-MRS provided no additional information for differentiating between meningiomas and gliomas. Proton MRS may be a beneficial adjunct to conventional MRI in patients with high clinical suspicion of inflammatory or neoplastic intracranial lesions.

Taverna G, Tidu L, Grizzi F, et al.
Olfactory system of highly trained dogs detects prostate cancer in urine samples.
J Urol. 2015; 193(4):1382-7 [PubMed] Related Publications
PURPOSE: We established diagnostic accuracy in terms of the sensitivity and specificity with which a rigorously trained canine olfactory system could recognize specific volatile organic compounds of prostate cancer in urine samples.
MATERIALS AND METHODS: Two 3-year-old female German Shepherd Explosion Detection Dogs were trained to identify prostate cancer specific volatile organic compounds in urine samples. They were tested on 362 patients with prostate cancer (range low risk to metastatic) and on 540 healthy controls with no nonneoplastic disease or nonprostatic tumor. This cross-sectional design for diagnostic accuracy was performed at a single Italian teaching hospital and at the Italian Ministry of Defense Military Veterinary Center.
RESULTS: For dog 1 sensitivity was 100% (95% CI 99.0-100.0) and specificity was 98.7% (95% CI 97.3-99.5). For dog 2 sensitivity was 98.6% (95% CI 96.8-99.6) and specificity was 97.6% (95% CI 95.9-98.7). When considering only men older than 45 years in the control group, dog 1 achieved 100% sensitivity and 98% specificity (95% CI 96-99.2), and dog 2 achieved 98.6% sensitivity (95% CI 96.8-99.6) and 96.4% specificity (95% CI 93.9-98.1). Analysis of false-positive cases revealed no consistent pattern in participant demographics or tumor characteristics.
CONCLUSIONS: A trained canine olfactory system can detect prostate cancer specific volatile organic compounds in urine samples with high estimated sensitivity and specificity. Further studies are needed to investigate the potential predictive value of this procedure to identify prostate cancer.

Stoewen DL, Coe JB, MacMartin C, et al.
Qualitative study of the communication expectations of clients accessing oncology care at a tertiary referral center for dogs with life-limiting cancer.
J Am Vet Med Assoc. 2014; 245(7):785-95 [PubMed] Related Publications
OBJECTIVE: To describe the process aspects (communication) of the information expectations of clients accessing oncology care services at a tertiary referral center for dogs with life-limiting cancer.
DESIGN: Qualitative analysis of data acquired during in-person single and dyadic interviews.
SAMPLE: 43 dog owners participating in 30 interviews.
PROCEDURES: Independent in-person interviews were conducted with standardized open- and closed-ended questions from April to October 2009. Thematic analysis was performed on transcripts of the interview discussions.
RESULTS: The participants expected information to be communicated in a forthright manner; in multiple formats; with understandable language; in an unrushed environment wherein staff took the time to listen, answer all questions, and repeat information when necessary; on a continuous basis, with 24-hour access to address questions or concerns; in a timely manner; with positivity; with compassion and empathy; with a nonjudgmental attitude; and through staff with whom they had established relationships.
CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the manner in which information is communicated is vitally important to clients of dogs with life-limiting cancer in that it not only facilitates comprehension but also creates a humanistic environment from which clients derive the psychosocial support needed to successfully cope with their pet's condition.

Stoewen DL, Coe JB, MacMartin C, et al.
Qualitative study of the information expectations of clients accessing oncology care at a tertiary referral center for dogs with life-limiting cancer.
J Am Vet Med Assoc. 2014; 245(7):773-83 [PubMed] Related Publications
OBJECTIVE: To evaluate the content aspects of the information expectations of clients accessing oncology care services at a tertiary referral center for dogs with life-limiting cancer.
DESIGN: Qualitative analysis of data acquired during in-person single and dyadic interviews. Sample-43 dog owners participating in 30 interviews.
PROCEDURES: Independent in-person interviews were conducted with standardized open- and closed-ended questions from April to October 2009. Thematic analysis was performed on transcripts of the interview discussions.
RESULTS: For the clients, the central qualification was that the information given had to be the truth. Information was expected about all aspects of their dog's cancer and its treatment, varying in relation to clients' basic understanding of cancer, their previous experience with cancer, and their information preferences. Provision of information generated the trust and confidence necessary to engage in treatment, the ability to make informed decisions, and the ability to be prepared for the future. Provision of information also engendered a sense of control and capability and fostered hope.
CONCLUSIONS AND CLINICAL RELEVANCE: When dealing with owners of dogs with life-limiting cancer, results indicated that in addition to abiding by the principle of truth-telling, it is important for health-care service providers to ascertain clients' understanding of and experiences with cancer as well as their information preferences and thereby adopt a tailored approach to information giving. Provision of information enabled client action and patient intervention but also enhanced clients' psychosocial well-being. Veterinary healthcare service providers can purposely provide information to build and sustain clients' ability to successfully cope with their pet's condition.

Mata M, Vera JF, Gerken C, et al.
Toward immunotherapy with redirected T cells in a large animal model: ex vivo activation, expansion, and genetic modification of canine T cells.
J Immunother. 2014; 37(8):407-15 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising antitumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells, we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells, we targeted HER2(+) OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2(+) canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR, we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy before conducting studies in humans.

Gracanin A, Voorwald FA, van Wolferen M, et al.
Marginal activity of progesterone receptor B (PR-B) in dogs but high incidence of mammary cancer.
J Steroid Biochem Mol Biol. 2014; 144 Pt B:492-9 [PubMed] Related Publications
Progesterone plays an important role in the normal development and carcinogenesis of the mammary gland. In vitro studies have shown that the canine progesterone receptor B (cPR-B), which is essential for mammary development in the mouse, does not transactivate reporter constructs containing progesterone response elements. Therefore, the question was raised whether the cPR-B was completely devoid of transactivation potential of endogenous progesterone regulated genes. Canine mammary cell lines expressing doxycycline-inducible cPR-B, human PR-B or a chimera in which the canine B-upstream segment (BUS) was replaced by a human BUS were treated for 24h with doxycycline, progesterone or a combination of the two. The expression profiling was subsequently performed using a dog-specific microarray and miRNA primers. Incubation of stably transfected cell lines with doxycycline or progesterone alone, did not change expression of any endogenous gene. Expression of activated human PR-B or the chimera of human BUS with the canine PR resulted in differential expression of >500 genes whereas the activated cPR-B regulated only a subset of 40 genes and to a limited extent. The relevance of the marginal transactivation potential or the consequence of a lack of cPR-B function for the carcinogenesis of mammary gland tumors is discussed.

Manesh JY, Shafiee R, Pedram B, et al.
Improving the diagnosis, treatment, and biology patterns of feline mammary intraepithelial lesions: a potential model for human breast masses with evidence from epidemiologic and cytohistopathologic studies.
Tumour Biol. 2014; 35(12):12109-17 [PubMed] Related Publications
In this study, the frequency of different types of mammary masses and their relationship with cytohistopathologic changes was investigated and data on history, macroscopic description, clinical examination and treatment were collected. To determine the prevalence and types of cytohistopathologic changes, mammary glands from 12 female cats were evaluated. The mean age of cats at the time of diagnosis was 11.5 ± 1.9 years (range 4-14 years), the mean gross size of the masses was 3.1 ± 2.4 cm, 4/12 (33.3 %) masses were ≤3.0 cm in diameter, and the maximum diameter of the largest mass had a median of 5 cm, with a range of diameter of 6 × 5 × 4 cm. Moreover, the preferential localization of mammary masses was the abdominal lobes (%50) and thoracic lobes (%33.3), and inguinal lobes (%16.7 of cases). Furthermore, two cases of the inguinal masses affected the caudo-inguinal lobe, six cases caudo-abdominal lobe, and thoracic masses were found in four cases. Eventually, six cases (%50) of masses were found in the right mammary lobes and six cases (%50) in the left mammary lobes. The majority of the masses revealed elastic (%50 of cases), hard (%25 of cases), or soft (%25 of cases) consistency. In the present study, according to the criteria of the veterinary and the medical WHO classification system, of the 12 cats with the cytohistopathological features of six (50 %) cases qualified abscess, 3 (25 %) cases as cystic hyperplasia and 3 (25 %) cases were called situ carcinoma. Whereas, all hyperplastic lesions (case nos. 7-9 and ranging in size from, 1 to >4 cm(3)) and carcinomas in situ lesions (case nos. 10-12 and ranging in size from, 1 to >3 cm(3)) were found incidentally upon routine cytohistology. Other lesions were observed grossly and removed either at surgery (case nos. 1-6). Finally, the cats were treated with unilateral lumpectomy (3 cases) and also, nine (75 %) cases had subsequent drainage, 3 (25 %) of which showed cystic hyperplasia and 6 (50 %) showed abscess on subsequent histopathological evaluation. Therefore, a correct diagnosis must be established quickly, and treatment must be instituted rapidly when alteration is noted in the mammary glands.

Hussain N, Rahman N, Rehman A
Calcified amorphous tumors (CATs) of the heart.
Cardiovasc Pathol. 2014 Nov-Dec; 23(6):369-71 [PubMed] Related Publications
Intracavitary cardiac masses include neoplastic and nonneoplastic masses, which may share overlapping clinical symptomatology, physical examination findings, and or imaging characteristics. Definitive diagnosis of a cardiac mass is usually made on surgical excision and histological examination. In this article, we focus on one of the rare nonneoplastic cardiac mass, namely, calcified amorphous tumors. We present a series of three patients, an 80-year-old female who presented to the hospital for evaluation of a near syncope event, a 69-year-old female who presented for evaluation of palpitations, and a 60-year-old female who presented for evaluation of shortness of breath, who were found to have calcified amorphous tumors. We have also provided a relevant review of the literature on this topic.

Liu D, Xiong H, Ellis AE, et al.
Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer.
Cancer Res. 2014; 74(18):5045-56 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, seem to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated and are abnormally enriched with active histone modification H4-acetylation, whereas aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations, whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research.

Rathore K, Cekanova M
Animal model of naturally occurring bladder cancer: characterization of four new canine transitional cell carcinoma cell lines.
BMC Cancer. 2014; 14:465 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
BACKGROUND: Development and further characterization of animal models for human cancers is important for the improvement of cancer detection and therapy. Canine bladder cancer closely resembles human bladder cancer in many aspects. In this study, we isolated and characterized four primary transitional cell carcinoma (K9TCC) cell lines to be used for future in vitro validation of novel therapeutic agents for bladder cancer.
METHODS: Four K9TCC cell lines were established from naturally-occurring canine bladder cancers obtained from four dogs. Cell proliferation rates of K9TCC cells in vitro were characterized by doubling time. The expression profile of cell-cycle proteins, cytokeratin, E-cadherin, COX-2, PDGFR, VEGFR, and EGFR were evaluated by immunocytochemistry (ICC) and Western blotting (WB) analysis and compared with established human bladder TCC cell lines, T24 and UMUC-3. All tested K9TCC cell lines were assessed for tumorigenic behavior using athymic mice in vivo.
RESULTS: Four established K9TCC cell lines: K9TCC#1Lillie, K9TCC#2Dakota, K9TCC#4Molly, and K9TCC#5Lilly were confirmed to have an epithelial-cell origin by morphology analysis, cytokeratin, and E-cadherin expressions. The tested K9TCC cells expressed UPIa (a specific marker of the urothelial cells), COX-2, PDGFR, and EGFR; however they lacked the expression of VEGFR. All tested K9TCC cell lines confirmed a tumorigenic behavior in athymic mice with 100% tumor incidence.
CONCLUSIONS: The established K9TCC cell lines (K9TCC#1Lillie, K9TCC#2Dakota, K9TCC#4Molly, and K9TCC#5Lilly) can be further utilized to assist in development of new target-specific imaging and therapeutic agents for canine and human bladder cancer.

Knapp DW, Ramos-Vara JA, Moore GE, et al.
Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development.
ILAR J. 2014; 55(1):100-18 [PubMed] Related Publications
Each year more than 65,000 people are diagnosed with urinary bladder cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to improve the management of bladder cancer. Naturally occurring bladder cancer in dogs very closely mimics human invasive bladder cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder cancer complements experimentally induced rodent tumors in regard to animal models of bladder cancer. Results of cellular and molecular studies and -omics analyses in dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as dogs. Clinical treatment trials in pet dogs with TCC are considered a win-win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using dogs with naturally occurring TCC.

Fenger JM, London CA, Kisseberth WC
Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology.
ILAR J. 2014; 55(1):69-85 [PubMed] Related Publications
Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs.

Alvarez CE
Naturally occurring cancers in dogs: insights for translational genetics and medicine.
ILAR J. 2014; 55(1):16-45 [PubMed] Related Publications
Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog models are attractive, because they are genetically more similar to humans, share environmental exposures with their owners, suffer from the same diseases as humans, and receive a high level of health care. They are ideal for the study of chronic diseases, because they age five to eight times faster than humans and generally live to old age. In addition, each dog breed is on the order of 100-fold genetically simpler than the whole human or dog population. These traits make the dog ideal for the study of complex genetics of naturally occurring cancers. Here, we contrast the relative strengths of cancer genetics in humans and dogs. We propose that humans are most ideal for the study of somatic cancer genetics, whereas dogs are most ideal for germline genetics. That proposition is supported by comparison of genome-wide association studies (GWASs) in human and canine cancer. One of the advantages of dog cancer GWASs is the ability to rapidly map complex traits, conduct fine mapping and identification of causative variation, and thus be in a position to move on to functional studies. We mention how these strengths of dog models will lead to rapid advances in translational medicine.

Rodriguez CO
Using canine osteosarcoma as a model to assess efficacy of novel therapies: can old dogs teach us new tricks?
Adv Exp Med Biol. 2014; 804:237-56 [PubMed] Related Publications
Since its domestication more than 10,000 years ago, the dog has been the animal that most intimately shares our work and homelife. Interestingly, the dog also shares many of our diseases including cancer such as osteosarcoma. Like the human, osteosarcoma is the most common bone malignancy of the dog and death from pulmonary metastasis is the most common outcome. The incidence of this spontaneous bone neoplasm occurs ten times more frequently that it does so in children with about 8,000-10,000 cases estimated to occur in dogs in the USA. Because there is no "standard of care" in veterinary medicine, the dog can also serve us by being a model for this disease in children. Although the most common therapy for the dog with osteosarcoma is amputation followed by chemotherapy, not all owners choose this route. Consequently, novel therapeutic interventions can be attempted in the dog with or without chemotherapy that could not be done in humans with osteosarcoma due to ethical concerns. This chapter will focus on the novel therapies in the dog that have been reported or are in veterinary clinical trials at the author's institution. It is hoped that collaboration between veterinary oncologists and pediatric oncologists will lead to the development of novel therapies for (micro- or macro-) metastatic osteosarcoma that improve survival and might ultimately lead to a cure in both species.

Gracanin A, Timmermans-Sprang EP, van Wolferen ME, et al.
Ligand-independent canonical Wnt activity in canine mammary tumor cell lines associated with aberrant LEF1 expression.
PLoS One. 2014; 9(6):e98698 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1) and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand-independent mechanisms.

Königsbrügge O, Pabinger I, Ay C
Risk factors for venous thromboembolism in cancer: novel findings from the Vienna Cancer and Thrombosis Study (CATS).
Thromb Res. 2014; 133 Suppl 2:S39-43 [PubMed] Related Publications
Venous thromboembolism (VTE) occurs frequently in patients with cancer and contributes to elevated morbidity and mortality. Risk factors for the occurrence of VTE events in patients with cancer have been investigated in numerous clinical studies. For now more than 10 years, the Vienna Cancer and Thrombosis Study (CATS) has focused on the identification of parameters predictive of future VTE occurrence. CATS has contributed to new findings, which may help identify patients at high risk of developing VTE, by means of biomarkers (such as D-dimer, prothrombin fragment 1+2, soluble P-selectin, platelet count, coagulation factor VIII activity, thrombin generation potential, etc.). The association of tissue factor bearing microparticles and the mean platelet volume with the risk of VTE was also elaborately investigated in the framework of CATS. More recently CATS has researched clinical and clinicopathologic parameters which contribute to identification of patients at risk of VTE. The type of cancer is one of the most important risk factor for VTE occurrence. Also the stage of cancer and the histological grade of a tumor have been found to be associated with the occurrence of cancer-related VTE. In further investigations, venous diseases including a history of previous VTE, a history of superficial thrombophlebitis and the presence of varicose veins, have been associated with the risk of VTE in CATS.

Habineza Ndikuyeze G, Gaurnier-Hausser A, Patel R, et al.
A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma.
PLoS One. 2014; 9(5):e95404 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.

Singer J, Fazekas J, Wang W, et al.
Generation of a canine anti-EGFR (ErbB-1) antibody for passive immunotherapy in dog cancer patients.
Mol Cancer Ther. 2014; 13(7):1777-90 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuximab in human clinical oncology, we present here a "caninized" version of this antibody, can225IgG, for comparative oncology studies. Variable region genes of 225, the murine precursor of cetuximab, were fused with canine constant heavy gamma and kappa chain genes, respectively, and transfected into Chinese hamster ovary (CHO) DUKX-B11 cells. Of note, 480 clones were screened and the best clones were selected according to productivity and highest specificity in EGFR-coated ELISA. Upon purification with Protein G, the recombinant cetuximab-like canine IgG was tested for integrity, correct assembly, and functionality. Specific binding to the surface of EGFR-overexpressing cells was assessed by flow cytometry and immunofluorescence; moreover, binding to canine mammary tissue was demonstrated by immunohistochemistry. In cell viability and proliferation assays, incubation with can225IgG led to significant tumor cell growth inhibition. Moreover, this antibody mediated significant tumor cell killing via phagocytosis in vitro. We thus present here, for the first time, the generation of a canine IgG antibody and its hypothetical structure. On the basis of its cetuximab-like binding site, on the one hand, and the expression of a 91% homologous EGFR molecule in canine cancer, on the other hand, this antibody may be a promising research compound to establish passive immunotherapy in dog patients with cancer.

Ferraresso S, Bresolin S, Aricò A, et al.
Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
PLoS One. 2014; 9(4):e92707 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibitor 2 (TFPI-2) is a tumor suppressor involved in invasiveness inhibition. Although TFPI-2 transcriptional silencing, through promoter hypermethylation, has been widely reported in several human malignancies, it has never been explored in lymphoma. In the present study TFPI-2 methylation and gene expression have been investigated in canine Diffuse Large B-cell lymphomas (cDLBCL). The methylation level of 23 CpGs located within the TFPI-2 promoter was investigated by bisulfite-specific PCR and next generation amplicon deep sequencing (GS Junior 454, Roche) in 22 cDLBCLs and 9 controls. For the same specimens, TFPI-2 gene expression was assessed by means of Real-time RT-PCR. Sequence analysis clearly demonstrated that TFPI2 is frequently hypermethylated in cDLBCL. Hypermethylation of the TFPI-2 promoter was found in 77% of DLBCLs (17 out of 22) and in one normal lymph node. Globally, dogs with DLBCL showed a mean methylation level significantly increased compared to controls (p<0.01) and analysis of hypermethylation by site identified 19 loci out of 23 (82%) with mean methylation levels from 2- to 120-fold higher in cDLBCL. Gene expression analysis confirmed a significant down-regulation of TFPI-2 (p<0.05) in DLBCLs compared with normal lymph nodes, suggesting that TFPI-2 hypermethylation negatively regulates its transcription. In addition, a significant positive correlation (p<0.01) was found between TFPI-2 methylation levels and age providing the first indication of age-associated epigenetic modifications in canine DLBCL. To conclude, our findings demonstrated that epigenetic dysregulation of TFPI-2, leading to its reduced expression, is frequently detected in canine DLBCL. In the next future, the aberrant TFPI-2 promoter hypermethylation may be considered in association with prognosis and therapy.

Carvalho MI, Pires I, Prada J, Queiroga FL
A role for T-lymphocytes in human breast cancer and in canine mammary tumors.
Biomed Res Int. 2014; 2014:130894 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

Ito D, Frantz AM, Modiano JF
Canine lymphoma as a comparative model for human non-Hodgkin lymphoma: recent progress and applications.
Vet Immunol Immunopathol. 2014; 159(3-4):192-201 [PubMed] Related Publications
The term "lymphoma" describes a heterogeneous group of disorders involving monoclonal proliferation of malignant lymphocytes. As a group, lymphomas are among the most common tumors of dogs. Yet our enumeration and understanding of the many subtypes of lymphoma have been relatively slow, perhaps in part because for many years lymphoma was treated as a singular entity rather than a group of distinct diseases. The recognition that the full spectrum of lymphoid malignancies seen in humans also occurs in dogs, and that these tumors retain not only morphologic similarities and biological behavior but also synonymous driver molecular abnormalities, sets an ideal stage for dual-purpose research that can accelerate progress for these diseases in both species. Specifically, dogs represent exceptional models for defining causality, understanding progression, and developing new treatments for lymphoma in comparatively brief windows of time. Unique advantages of canine models include (1) spontaneous disease occurring without an isogenic background or genetic engineering; (2) chronology of disease adapted to lifespan, (3) shared environment and societal status that allows dogs to be treated as "patients," while at the same time being able to ethically explore translational innovations that are not possible in human subjects; and (4) organization of dogs into breeds with relatively homogeneous genetic backgrounds and distinct predisposition for lymphomas. Here, we will review recent studies describing intrinsic and extrinsic factors that contribute to the pathogenesis of canine and human lymphomas, as well as newly developed tools that will enhance the fidelity of these models to improve diagnosis and develop new treatments.

Paoloni M, Webb C, Mazcko C, et al.
Prospective molecular profiling of canine cancers provides a clinically relevant comparative model for evaluating personalized medicine (PMed) trials.
PLoS One. 2014; 9(3):e90028 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
BACKGROUND: Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting.
METHODOLOGY: A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type.
CONCLUSIONS: Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (<1 week). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development.

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